This invention relates to certain pyrimidines and pyridines, their N-oxides, agriculturally suitable salts, compositions thereof, and methods of their use for controlling undesirable vegetation.
The control of undesired vegetation is extremely important in achieving high crop efficiency. Achievement of selective control of the growth of weeds especially in such useful crops as rice, soybean, sugar beet, corn (maize), potato, wheat, barley, tomato and plantation crops, among others, is very desirable. Unchecked weed growth in such useful crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of undesired vegetation in noncrop areas is also important. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action.
EP 723,960 discloses herbicidal substituted pyrimidines and pyridines of Formula i: 
wherein, inter alia,
A is an optionally substituted aryl or 5- or 6-membered nitrogen containing heteroaromatic group;
X is oxygen or sulfur;
Z is nitrogen or CH;
R1 and R2 are independently hydrogen, halogen, alkyl, haloalkyl, nitro or cyano;
n is 0, 1 or 2; and
m is 0 to 5.
The pyrimidines and pyridines of the present invention are not disclosed in this reference.
This invention is directed to compounds of Formula I including all geometric and stereoisomers, N-oxides, and agriculturally suitable salts thereof, as well as agricultural compositions containing them and a method of their use for controlling undesirable vegetation: 
W is N or CR11;
X, Y and Z are independently N or CR12;
R1 and R2 are independently H, halogen, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 alkoxyalkyl, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkoxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 alkenyloxy, C3-C4 alkynyloxy, S(O)nR13, C2-C4 alkylthioalkyl, C2-C4 alkylsulfonylalkyl, C1-C4 alkylamino or C2-C4 dialkylamino;
R3 is H, F, Cl, Br, cyano, C1-C4 alkyl, C1-C4 haloalkyl or CO2R14;
R4 is H, F, C1-C4 alkyl, OH or OR14;
R3 and R4 can be taken together with the carbon to which they are attached to form C(xe2x95x90O) or C(xe2x95x90NOR14);
R5 is halogen, cyano, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-4 haloalkoxy or S(O)nR13;
R6 and R10 are independently H, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or S(O)nR13;
R7 is halogen, cyano, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or S(O)nR13;
R8 is C1-C4 alkyl or C1-C4 haloalkyl;
R9 is H, halogen, cyano, SF5, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C4 alkenyloxy, C3-C4 alkynyloxy or S(O)nR13;
R11 is H, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or S(O)nR13;
R12 is H, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or S(O)nR13;
each R13 is independently C1-C4 alkyl or C1-C4 haloalkyl;
each R14 is independently C1-C4 alkyl; and
each n is independently 0, 1 or 2.
In the above recitations, the term xe2x80x9calkylxe2x80x9d, used either alone or in compound words such as xe2x80x9calkylthioxe2x80x9d or xe2x80x9chaloalkylxe2x80x9d includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. The term xe2x80x9c1-2 alkylxe2x80x9d indicates that one or two of the available positions for that substituent may be alkyl which are independently selected. xe2x80x9cAlkenylxe2x80x9d includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. xe2x80x9cAlkenylxe2x80x9d also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. xe2x80x9cAlkynylxe2x80x9d includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. xe2x80x9cAlkynylxe2x80x9d can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. xe2x80x9cAlkoxyxe2x80x9d includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. xe2x80x9cAlkoxyalkylxe2x80x9d denotes alkoxy substitution on alkyl. Examples of xe2x80x9calkoxyalkylxe2x80x9d include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. xe2x80x9cAlkenyloxyxe2x80x9d includes straight-chain or branched alkenyloxy moieties. Examples of xe2x80x9calkenyloxyxe2x80x9d include H2Cxe2x95x90CHCH2O, (CH3)2Cxe2x95x90CHCH2O, (CH3)CHxe2x95x90CHCH2O, (CH3)CHxe2x95x90C(CH3)CH2O and CH2xe2x95x90CHCH2CH2O. xe2x80x9cAlkynyloxyxe2x80x9d includes straight-chain or branched alkynyloxy moieties. Examples of xe2x80x9calkynyloxyxe2x80x9d include HCxe2x89xa1CCH2O, CH3Cxe2x89xa1CCH2O and CH3Cxe2x89xa1CCH2CH2O. xe2x80x9cAlkylthioxe2x80x9d includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. xe2x80x9cAlkylthioalkylxe2x80x9d denotes alkylthio substitution on alkyl. Examples of xe2x80x9calkylthioalkylxe2x80x9d include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. xe2x80x9cAlkylsulfinylxe2x80x9d includes both enantiomers of an alkylsulfinyl group. Examples of xe2x80x9calkylsulfinylxe2x80x9d include CH3S(O), CH3CH2S(O), CH3CH2CH2S(O), (CH3)2CHS(O) and the different butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers. Examples of xe2x80x9calkylsulfonylxe2x80x9d include CH3S(O)2, CH3CH2S(O)2, CH3CH2CH2S(O)2, (CH3)2CHS(O)2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers. xe2x80x9cAlkylaminoxe2x80x9d, xe2x80x9cdialkylaminoxe2x80x9d, xe2x80x9calkenylthioxe2x80x9d, xe2x80x9calkenylsulfinylxe2x80x9d, xe2x80x9calkenylsulfonylxe2x80x9d, xe2x80x9calkynylthioxe2x80x9d, xe2x80x9callynylsulfinylxe2x80x9d, xe2x80x9calkynylsulfonylxe2x80x9d, and the like, are defined analogously to the above examples. One skilled in the art will appreciate that not all nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are very well known by one skilled in the art including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.
The term xe2x80x9chalogenxe2x80x9d, either alone or in compound words such as xe2x80x9chaloalkylxe2x80x9d, includes fluorine, chlorine, bromine or iodine. The term xe2x80x9c1-2 halogenxe2x80x9d indicates that one or two of the available positions for that substituent may be halogen which are independently selected. Further, when used in compound words such as xe2x80x9chaloalkylxe2x80x9d, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of xe2x80x9chaloalkylxe2x80x9d include F3C, ClCH2, CF3CH2 and CF3CCl2. Examples of xe2x80x9chaloalkoxyxe2x80x9d include CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O.
The total number of carbon atoms in a substituent group is indicated by the xe2x80x9cCi-Cjxe2x80x9d prefix where i and j are numbers from 1 to 4. For example, C1-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl; C2 alkoxyalkyl designates CH3OCH2; C3 alkoxyalkyl designates, for example, CH3CH(OCH3), CH3OCH2CH2 or CH3CH2OCH2; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2 and CH3CH2OCH2CH2. Examples of xe2x80x9calkylcarbonylxe2x80x9d include C(O)CH3, C(O)CH2CH2CH3 and C(O)CH(CH3)2. Examples of xe2x80x9calkoxycarbonylxe2x80x9d include CH3OC(xe2x95x90O), CH3CH2OC(xe2x95x90O), CH3CH2CH2OC(xe2x95x90O), (CH3)2CHOC(xe2x95x90O) and the different butoxy- or pentoxycarbonyl isomers. In the above recitations, when a compound of Formula I is comprised of one or more heterocyclic rings, all substituents are attached to these rings through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
When a group contains a substituent which can be hydrogen, for example R9, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
The compounds of this invention thus include compounds of Formula I, geometric and stereoisomers thereof, N-oxides thereof, and agriculturally suitable salts thereof. The compound of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
The salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
Preferred compounds of the invention for reasons of better activity and/or ease of synthesis are:
Preferred 1. Compounds of Formula I above, geometric or stereoisomers thereof, N-oxides thereof and agriculturally-suitable salts thereof, wherein
R1 and R2 are independently H, C1-C4 alkyl or C1-C4 alkoxy;
R5 and R7 are independently halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy or S(O)nR13;
R6 is H or F;
R8 is C1-C4 alkyl;
R9 is halogen, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkyl, C1-C4 haloalkyl or S(O)nR13;
R10 is H, halogen, cyano or C1-C4 haloalkyl;
R11 is H, halogen, cyano or C1-C4 haloalkyl;
R12 is H, halogen, cyano or C1-C4 haloalkyl; and
n is 0.
Preferred 2. Compounds of Preferred 1 wherein
W is N;
R5 and R7 are independently C1-C4 haloalkyl or C1-C4 haloalkoxy; and
R9 is halogen, C1-C4 haloalkoxy, C1-C4 haloalkyl or S(O)nR13.
Preferred 3. Compounds of Preferred 2 wherein
R1 is C1-C4 alkyl or C1-C4 alkoxy;
R2 is H;
R3 and R4 are independently H, F or methyl;
R5 and R7 are independently C1-C2 haloalkyl or C1-C2 haloalkoxy; and
R9 is C1-C2 haloalkoxy, C1-C2 haloalkyl or S(O)nR13.
Preferred 4. Compounds of Preferred 3 wherein
J is J-1, J-5 or J-7.
Preferred 5. Compounds of Preferred 2 wherein
R3 and R4 can be taken together with the carbon to which they are attached to form C(xe2x95x90O).
Preferred 6. Compounds of Preferred 5 wherein
R1 is C1-C4 alkyl or C1-C4 alkoxy;
R2 is H;
R5 and R7 are independently C1-C2 haloalkyl or C1-C2 haloalkoxy; and
R9 is C1-C2 haloalkoxy, C1-C2 haloalkyl or S(O)nR13.
Preferred 7. Compounds of Preferred 5 wherein
J is J-1 or J-5.
Most preferred is the compound of Formula I selected from the group consisting of:
(a) 5-ethyl-4-[[3-(trifluoromethoxy)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine;
(b) 5-ethyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine;
(c) 5-methyl-2-[4-(trifluoromethyl)phenyl]-4-[[3-(trifluoromethyl)phenyl]methyl]pyrimidine;
(d) 5-methyl-4-[[3-(trifluoromethoxy)phenyl]methyl]-2-[4-(trifluoromethyl)phenyl]pyrimidine;
(e) 5-methyl-4-[[3-(trifluoromethoxy)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine;
(f) [5-methyl-2-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl][3-(trifluoromethyl)phenyl]methanone;
(g) [5-methyl-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-4-pyrimidinyl][3-(trifluoromethyl)phenyl]methanone; and
(h) 5-methyl-4-[[3-(trifluoromethyl)phenyl]methyl]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine.
This invention also relates to herbicidal compositions comprising herbicidally effective amounts of the compounds of the invention and at least one of a surfactant, a solid diluent or a liquid diluent. The preferred compositions of the present invention are those which comprise the above preferred compounds.
This invention also relates to a method for controlling undesired vegetation comprising applying to the locus of the vegetation herbicidally effective amounts of the compounds of the invention (e.g., as a composition described herein). The preferred methods of use are those involving the above preferred compounds.
The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-12. The definitions of J, A, W, X, Y, Z, R1, R2, R3, R4, R9, R10, and R14 in the compounds of Formulae 1-16 below are as defined above in the Summary of the Invention. Compounds of Formulae Ia-Ic are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-Ic are as defined above for Formula I.
Scheme 1 illustrates the preparation of compounds of Formula Ia (Formula I wherein A is A-1). Substituted heterocycles of Formula 1 (where L1 is halogen) can be coupled with metalated aryls or heteroaryls of Formula 2 (where Met is Sn(alkyl)3, B(OH)2 or Zn(L1)2) in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) or in the presence of a palladium(II) catalyst such as dichlorobis(triphenylphosphine)palladium(II) to provide compounds of Formula Ia. Palladium(II) catalysts are generally used with a suitable base such as aqueous sodium bicarbonate or sodium carbonate. Suitable solvents for this coupling include N,N-dimethylformamide, dimethoxyethane, acetonitrile or tetrahydrofuran. Reaction temperatures range from 20xc2x0 C. to 130xc2x0 C. 
Scheme 2 illustrates the preparation of compounds of Formula Ib (Formula I wherein A is A-2). Substituted heterocycles of Formula 1 are allowed to react with substituted azoles of Formula 3 in the presence of a suitable base such as an alkali carbonate, alkali hydroxide, or alkali hydride in a solvent such as N,N-dimethylfornamide, acetonitrile or tetrahydrofuran at temperatures ranging from 0xc2x0 C. to 130xc2x0 C. to provide compounds of Formula Ib. 
Scheme 3 illustrates a method for preparing compounds of Formula Ic wherein J is an azole heterocycle of Formula J-7 and A is A-1 or A-2. Compounds of Formula 4 are allowed to react with an azole heterocycle of Formula 3 in a protic or aprotic solvent at temperatures ranging from 0xc2x0 C. to 100xc2x0 C. in the presence of a suitable base such an alkali carbonate, alkali hydroxide, or alkali hydride to provide compounds of Formula Ic. Particularly suitable are potassium carbonate as base and acetonitrile or N,N-dimethylformamide as solvent at a reaction temperature range of 20xc2x0 C. to 80xc2x0 C. 
Substituted pyrimidine intermediates of Formula 1 (wherein J is J-1 to J-6) can be prepared by the method shown in Scheme 4. By the synthetic protocol of Menta, E. and Oliva, A. J. Heterocyclic Chem. (1997), 34, p 27, a dihalopyrimidine of Formula 5 (where L1 and L2 are halogen) is coupled with a substituted alkyl zinc reagent of Formula 6 (where L3 is halogen) in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) or in the presence of a palladium(II) catalyst such as dichloro-bis(triphenylphosphine)palladium(II). Palladium(II) catalysts are generally used with a suitable base such as sodium bicarbonate or sodium carbonate. Suitable solvents for this coupling include N,N-dimethylformamide, dimethoxyethane, acetonitrile or tetrahydrofuran. Reaction temperatures range from 0xc2x0 C. to 130xc2x0 C. 
Metalated aryls and heteroaryls of Formula 2 can be obtained commercially or can be prepared by methods known in the art: Sandosham, J. and Undheim, K. Tetrahedron (1994), 50, pp 275-284; Undheim, K. and Benneche, T. Acta Chemica Scandinavica (1993), 47, pp 102-121; Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1995; volume 62, pp 305-418.
Azoles of Formula 3 can be obtained commercially or can be prepared by methods known in the art Elguero, J. et al., Organic Preparations and Procedures Int. (1995), 27, pp 33-74; Comprehensive Heterocyclic Chemistry; Potts, K., Ed.; Pergamon Press: New York, 1984; volume 5, chapters 4.04-4.13; Heterocyclic Compounds; Elderfield, R., Ed.; John Wiley: New York, 1957; volume 5, chapters 2 and 4; Baldwin, J. et al. J. Med. Chem., (1975), 18, pp 895-900; Evans, J. J. et al. U.S. Pat. No. 4,038,405.
Dihaloheterocycles of Formula 5 can be obtained commercially or can be readily prepared by known methods in the art; for example, see Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1993; volume 58, pp 301-305; Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley: New York, 1957; volume 6, chapter 7, pp 265-270.
Zinc reagents of Formula 6 can be made by the method shown in Scheme 5. A substituted alkyl halide of Formula 7 (where L3 is halogen) is allowed to react with activated zinc (see Jubert, C. and Knochel, P. J. Org. Chem. (1992), 57, p 5425; Knochel, P. and Singer, R. D. Chem. Rev. (1993), 93, p 2117) in a suitable solvent such as N,N-dimethylformamide, dimethoxyethane, acetonitrile or tetrahydrofuran. Reaction temperatures range from 0xc2x0 C. to 130xc2x0 C. 
As shown in Scheme 6, heterocyclic benzylic bromides of Formula 4 can be made by bromination of heterocycles of Formula 8 with bromine in an acidic solvent such as acetic acid at temperatures ranging from 20xc2x0 C. to 100xc2x0 C. (see, for example, Strekowski et al. J. Org. Chem. (1992), 56, p 5610). 
Heterocycles of Formula 8 can be made from precursor heterocycles of Formula 9 as shown in Scheme 7. The addition of lithium or Grignard reagents of formula R3R4CHLi or R3R4CHMgL1 to heterocycles of Formula 9 is carried out in ethereal solvents such as ether or tetrahydrofuran at temperatures ranging from xe2x88x9270xc2x0 C. to 30xc2x0 C. The reaction mixture is worked up by the addition of water and an oxidizing agent. A particularly suitable oxidizing agent is dichlorodicyanoquinone (DDQ). See Strekowski et al. J. Org. Chem. (1992), 56, p 5610 for examples of this synthetic method. 
Heterocycles of Formula 9 can be prepared according to methods taught by Strekowski et al. J. Org. Chem. (1992), 56, p 5610; Bredereck et. al., Chem. Ber. (1960), 93, p 1208; Burdeska et al. Helv. Chim. Acta (1981), 64, p 113; Undheim, K. and Benneche, T. Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1995, volume 62, pp 305-418; and Comprehensive Heterocyclic Chemistry; Boulton, A. J., and McKillop, A., Eds.; Pergamon Press: New York, 1984; volume 3, chapter 2.13. Lithium and Grignard reagents of formulae R3R4CHLi or R3R4CHMgL1 are commercially available or can be prepared by methods well known in the art.
Compounds of Formula 1 (wherein R3 and R4 are taken together as C(xe2x95x90O)) can be prepared by the condensation of pyrimidines and pyridines of Formula 10 with aldehydes of Formula 11 in the presence of an imidazolium catalyst of Formula 12 as shown in Scheme 8. This reaction is carried out in the presence of a strong base such as an alkali hydride, preferably sodium hydride, in solvents such as dichloromethane, dioxane, tetrahydrofuran, benzene, toluene or other aprotic solvent. The reaction may be carried out at temperatures between 0 and 120xc2x0 C. A wide variety of azolium salts are known to catalyze this transformation; see, for example, Miyashita Heterocycles, (1996), 43, 509-512 and references cited therein. A preferred catalyst is 1,3-dimethylimidazolium iodide. 
Compounds of Formula I (wherein R3 and R4 are taken together as C(xe2x95x90NOR14)) can be formed directly from compounds of Formula I (wherein R3 and R4 are taken together as C(xe2x95x90O)) by the action of hydroxylamine or capped hydroxylamine salts of Formula 13 as shown in Scheme 9. Many hydroxylamines are commercially available as acid salts and are freed by the action of a base in the presence of the ketone of Formula I. Suitable bases include alkali carbonates, acetates, and hydroxides. These reactions are best carried out in protic solvents, such as lower alcohols, at temperatures between 0 and 120xc2x0 C. Especially preferred conditions use sodium carbonate or sodium acetate as base in ethanol at 70 to 80xc2x0 C. 
Compounds of Formula I (wherein R3 is OH and R4 is H) can be made by the reduction of ketones of Formula I (wherein R3 and R4 are taken together as C(xe2x95x90O)) as shown in Scheme 10. A wide variety of reduction conditions can be utilized, but for reasons of ease of use and selectivity, alkali borohydrides are preferred reductants. The reduction can be carried out at 0 to 100xc2x0 C. in a variety of solvents which are inert to the action of borohydrides. Especially preferred conditions are the use of sodium borohydride in ethanol at 0 to 25xc2x0 C. 
As shown in Scheme 11, compounds of Formula 1 wherein J is J-7 can also be made via the bromination of compounds of Formula 14 with molecular bromine in an acidic solvent such as acetic acid at temperatures ranging from 20 to 100xc2x0 C. in the same way as previously described in Scheme 6. The brominated products of Formula 15 can be displaced by heterocycles of Formula 3 in the presence of a base such as potassium carbonate as previously described for Scheme 2. Compounds of Formula 14 are known in the literature or are commercially available. See Benneche (Acta Chemica Scandanavia, 1997, 51, 302) for preparation of these compounds from compounds of Formula 5. 
Compounds of Formula 1 in which R3 is cyano can be made as shown in Scheme 12. The reaction of acetonitrile derivatives of formula 16 with compounds of Formula 5 in the presence of a base gives compounds of formula 1 with a cyano group. The reaction can be carried out in a variety of solvents such as dimethylformamide, tetrahydrofuran, or other solvents inert to strong bases. A wide variety of bases which can deprotonate substituted acetonitriles can be used. Sodium hydride and potassium t-butoxide are preferred due to their ease of use and availability. The reaction can be carried out at temperatures ranging from 0 to 100xc2x0 C. Compounds of formula 16 are well known in the literature and many are commercially available 
Compounds of Formula I substituted with the group S(O)nR13 wherein n is 1 or 2 can be prepared from compounds of Formula I substituted with said S(O)nR13 group wherein n is 0 by treatment with an oxidizing reagent such as m-chloroperoxybenzoic acid or Oxone(copyright) (potassium peroxymonosulfate). This type of oxidation reaction is well known in the art; for example, see March, J. Advanced Organic Chemistry; John Wiley: New York, 1992; 4th edition, pp 1201-1203.
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I.
One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1H NMR spectra are reported in ppm downfield from tetramethylsilane; s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, br s=broad singlet.